Alginic acid is a soluble polysaccharide extracted mainly from brown algae such as Laminariales and Fucales species (Kakita et al., 2008, J Appl Phycol, 20:543-549). The alginate chain is made of the following regions: two homopolymeric regions of β-d-mannuronic acid (M) blocks and α-1-guluronic acid (G) blocks, interdispersed with regions of alternating structure of α-1-guluronic and β-d-mannuronic acid blocks (Wui, 2011, Journal of Pharmacy and Pharmacology, 63: 1497-1512). An insoluble gel composed of three-dimensional network is formed upon gelation process of alginate when blocks of guluronic acid residues interact ionically with divalent cations such as Ca+2. This network is usually described by the egg box model (Bajpai and Sharma, 2004, Reactive & Functional Polymers, 59:129-140).
Alginate is reported to be generally non-toxic, biodegradable, non-immunogenic and biocompatible. Thus, these advantages suggest that alginic beads may be suitable for oral administration (Wui, 2011, Journal of Pharmacy and Pharmacology, 63: 1497-1512). Sodium alginate is the salt of alginic acid. When small drops of sodium alginate solution are dropped into calcium chloride solution a cation exchange between Na+ and Ca2+ takes place and a spherical gel with regular shape and size is obtained. The spherical gel is termed ‘alginate bead’ (Kim and Lee, 1992, International Journal of Pharmaceutics, 79:11-19).
Alginate beads are insoluble and significantly reduce its swelling in the presence of the solvent as the degree of cross-linking increases. This generally results in a reduction of the permeability of different solutes. As a consequence, the release of embodied drugs in alginate matrices will be delayed, allowing these systems to be used in drug controlled release (Wang et al., 2010, Carbohydrate Polymers, 82: 842-847). However, degradation events can take place through loss of calcium alginate cross linkages through reaction of Ca2+ with PO43− which are removed by precipitation as Ca3(PO4)2 (Wui, 2011, Journal of Pharmacy and Pharmacology, 63: 1497-1512).
Alginates are among the most widely used biopolymers in the field of pharmaceutics. They are conventionally used as an excipient in drug products due to their thickening, gel-forming, and stabilizing properties (Tønnesen and Karlsen, 2002, Drug Development and Industrial Pharmacy, 28(6); 621-630). Alginate salt solution has the ability to form an insoluble gel in the presence of multivalent ions such as Ca++ and Zn++, which can be utilized to prepare multiparticulate systems-beads-incorporating numerous drugs, proteins, cells, or enzymes that can be released in a controlled manner (Smrdel et al., 2006, Drug Development and Industrial Pharmacy, 32:623-633). Ionotropic gelation is the commonly used method to produce alginate beads, where the dispersion of alginate and material to be incorporated is added drop wise into a multivalent ion solution (Smrdel et al., 2006, Drug Development and Industrial Pharmacy, 32:623-633). Therefore, alginate can play a significant role in the design of a tailored controlled-release product. However, limitations such as some difficulties in the preparation process, in addition to quality control challenges due to the small size of these beads limit the feasibility of producing them in large scale to be introduced into the market.
Alginate has been formulated into different dosage forms to deliver drugs orally. One of these dosage forms is calcium alginate beads (Wui, 2011, Journal of Pharmacy and Pharmacology, 63: 1497-1512). Generally, different methods can be used to manufacture beads such as: dripping emulsification and coacervation, rotating-disc atomization, air jet, atomization, electrostatic dripping, mechanical cutting, and the vibrating nozzle technique (Nussinovitch, 2010, Polymer Macro- and Micro-Gel Beads: Fundamentals and applications, Springer, 2010:2). However, some of these techniques suffer from different limitations. One of these limitations is the difficulty in achieving the simultaneous production of beads at a high production rate with a satisfactory level of material utilization under mild and non-toxic conditions or under completely sterile conditions. Another difficulty is the ability to scale-up the process that will produce beads with a narrow size distribution. (Nussinovitch, 2010, Polymer Macro- and Micro-Gel Beads: Fundamentals and applications, Springer, 2010:2). Also, there is a maximum concentration of polymer for producing spherical beads. This means that there is a limit to the capability to retarding the drug release. This limits its use as a controlled release polymer. Most importantly, the small size of the beads presents a major limitation due to high drug loss during bead preparation (Almeida and Almeida, 2004, Journal of Controlled Release, 97: 431-439).
Natural polymers have attracted a lot of attention in oral drug delivery due to their safety, biodegradability, and biocompatibility (Almeida and Almeida, 2004, Journal of Controlled Release, 97: 431-439). Sodium alginate is one of the biopolymers that has been formulated as microspheres, microcapsules, gel beads, hydrogel, film, nanoparticles and tablets due to the inert environment within its network which allows for the entrapment of a wide range of bioactive substances, cells and drug molecules (Pasparakis and Bouropoulos, 2006, International Journal of Pharmaceutics, 323:34-42). One of the unique properties of sodium alginate is its ability to form an insoluble gel when it comes in contact with divalent cations. Beads; called calcium alginate beads can be produced by dropping soluble sodium alginate gel drops into a calcium chloride solution. These beads have several limitations such as poor drug encapsulation due to their small size.
Osmotic delivery systems utilize osmotic pressure for controlled delivery of active agents. In these systems the release of drug(s) from osmotic systems follows zero-order kinetics. This is mainly governed by various formulation factors such as solubility, osmotic pressure of the core components, size of the delivery orifice, and nature of the rate-controlling membrane (Kunal and Mehta, 2013, International Journal of Pharmacy and Pharmaceutical Sciences, 5:1005-1013). For some of these systems the solubility of the drug is considered one of the most important parameters affecting drug release kinetics. Osmotic drug delivery systems can only deliver drugs with sufficient solubility so that the entire dose dissolves in the capsule. (about 1 mL) (Waterman et al., 2011, Journal of Controlled Release, 152: 264-269). According to Kunal et al., drugs with a density of unity and the solubility of ≤0.05 g/cm3 would be released with ≥95% zero-order kinetics. Highly water-soluble drugs would demonstrate a high release rate that would be zero-order for only a small percentage of the initial drug load. Hence, candidate drugs for osmotic delivery have water solubility in the range of 50-300 mg/ml (Kunal and Mehta, 2013, International Journal of Pharmacy and Pharmaceutical Sciences, 5:1005-1013). This issue has been addressed by osmotic capsules by Waterman K. C. and his colleagues (Waterman et al., 2011, Journal of Controlled Release, 152: 264-269). They developed an osmotic capsule that is independent of drug solubility or drug loading. They developed a capsule shell over the active tablet layer which has a hole drilled through it. This hole allows a stream of material to be extruded from the core once water imbibes through the semipermeable membrane and creates an API mixed suspension. This suspension is sufficiently viscous to suspend the API. However, it flows under the shear created by the combination of osmosis and pressure from the swelling layer to allow extrusion out of the hole in the coating.
Although osmotic capsules deliver drugs independent of drug solubility or drug load they suffer from several limitations. The rate of drug release is controlled through the thickness of the capsule shell. This dictates the water diffusion rate into the capsule core to create the resultant osmotic pressure (Waterman et al., 2011, Journal of Controlled Release, 152: 264-269). Thus, complete drug release in less than 6 hours is not feasible. The capsule thickness range is limited due to the mechanical constraints of placing two capsule together. Also, the manufacturing process needs high quality control management for:
A. Tablet manufacturing since all ingredients are in powder form.
B. Capsule orifice diameter.
C. Thickness of the capsule shell.
D. Thickness uniformity.
Applying current to a hydrogel as a mechanism to control drug release was previously studied (Kwon et al., 1991, Letters to Nature, 354: 291-293). Kwon proposed a solid matrix made with poly(ethyloxaline) and poly methacrylic acid (PMAA) as an implant. This matrix dissolves at pH 5.4 and precipitates at a lower pH. However, the procedure they used was complicated which limited its practical application.
In 1992, Yuk et al developed a composite of calcium alginate/polyacrylic acid to use it as an electric current-sensitive drug delivery system (Yuk et al., 1992, Pharmaceutical Research, 9(7):955-957). They observed a pulsatile drug release upon application of electric current. However, the way they prepared the calcium alginate composite suffered several limitations and made it difficult for practical application.
Thus, there remains a need in the art for novel methods for producing big and uniform dried alginate gel tablets, and optimized new formulations comprising various adjuvants. There also remains a need in the art for new models which can be used to formulate drug release profiles of novel calcium alginate dosage forms. There remains a need in the art for bigger, more uniform, tablet size calcium alginate dosage form that can be produced in a simple process with minimum quality control. There also remains a need in the art for tablets with a zero order release profile that can be easily adjusted by varying cross linking time and/or the concentration of the cross linking solution or by the use of additives. There also remains a need in the art for drug dosage forms that release the drug in an uniform manner regardless of the properties of the drug. There remains a need in the art for novel calcium alginate oral dosage forms which deliver drugs by electrochemical interaction, or fail-safe alginate tablets. This invention fulfils these needs.